The Role of Macrophages in Connective Tissue Disease-Associated Interstitial Lung Disease: Focusing on Molecular Mechanisms and Potential Treatment Strategies

Connective tissue disease-associated interstitial lung disease (CTD-ILD) is a severe manifestation of CTD that leads to significant morbidity and mortality. Clinically, ILD can occur in diverse CTDs. Pathologically, CTD-ILD is characterized by various histologic patterns, such as nonspecific interstitial pneumonia, organizing pneumonia, and usual interstitial pneumonia. Abnormal immune system responses have traditionally been instrumental in its pathophysiology, and various changes in immune cells have been described, especially in macrophages. This article first briefly overviews the epidemiology, clinical characteristics, impacts, and histopathologic changes associated with CTD-ILD. Next, it summarizes the roles of various signaling pathways in macrophages or products of macrophages in ILD, helped by insights gained from animal models. In the following sections, this review returns to studies of macrophages in CTD-ILD in humans for an overall picture of the current understanding. Finally, we direct attention to potential therapies targeting macrophages in CTD-ILD in investigation or in clinical trials, as well as the future directions regarding macrophages in the context of CTD-ILD. Although the field of macrophages in CTD-ILD is still in its infancy, several lines of evidence suggest the potential of this area.

Although the mechanisms contributing to ILD in the context of CTDs are not known in detail, the prevailing hypothesis suggests the involvement of abnormal inflammation and subsequent exaggerated fibrotic reactions [1]. Interestingly, macrophages not only coordinate inflammation process but also mediate the formation of fibrosis. Given these characteristics of macrophages, it makes sense that macrophages play critical roles in the pathogenesis of CTD-ILD. The roles of macrophages have been suggested in numerous studies. For example, macrophages in the lungs of SSc-ILD upregulated profibrotic factors that promoted lung fibroblast activation [25]. Another example is DM-ILD. Previous studies reported that ferritin was produced by macrophages [26] and correlated with lung function parameters and survival [27]. IL-18 was also secreted by macrophages [28], elevated in DM-ILD compared with DM without ILD [29], and correlated with the severity of pulmonary disease [30]. Together, these studies point to the importance of macrophages in the development and progression of CTD-ILD.
Macrophages are versatile cells that exhibit high plasticity according to crosstalk between macrophages and the tissue microenvironment. Historically, analogous to the Th1/Th2 dichotomy, studies have characterized macrophages as classically activated (M1) or alternatively activated (M2) according to the activation status. Although the dichotomous inflammatory M1/repair M2 model cannot fully represent the current understanding of macrophage biology in ILD, studies on fibrosis usually build upon this classification scheme. As one of the most versatile cell types with diverse immunity functions, macrophages not only initiate an inflammatory response after injury but are also involved in the injury resolution and repair. In other words, in the airway and lung microenvironment, macrophages orchestrate the development and establishment of ILD. In this process, macrophage products and/or macrophages themselves are implicated at each key step. Work utilizing ILD patient samples provided several pieces of evidence of altered macrophages in ILD, whose functional importance was further confirmed in murine models [31].
Radiologically, CTD-ILD is characterized by various patterns of fibrosis using highresolution computed tomography (HRCT) in the lung bases of patients with CTD, such as RA and SSc [32]. Most of our understanding of CTD-ILD comes from studies on pulmonary fibrosis (PF) in animal models. Therefore, we will first review the current knowledge of macrophages in the ILD/PF of animal models and then review recent advances in the molecular biology of CTD-ILD in the literature. Histopathological changes associated with DM-ILD are organizing pneumonia (OP), nonspecific interstitial pneumonia (NSIP), and usual interstitial pneumonia (UIP). Patients have increased palmar papules and myocardial involvement, with mortality rate of up to 24.62%. (2) The incidence of MPA-ILD is around 1.4/10 5 . The pathological patterns are often UIP and NSIP. It is associated with decreased renal function and has a mortality rate of up to 39%. (3) The estimated incidence of RA-ILD is 3.7/10 5 . It is characterized by UIP. The patients usually suffer from increased asthma, chronic obstructive pulmonary disease (COPD), diabetes, and heart disease, and the mortality rate is 8.08%. (4) The incidence of SSc-ILD is 1364/10 5 . It is characterized by NSIP and UIP, accompanied by COPD, gastroesophageal reflux disease (GERD), hypertension, and skin disorders and a mortality rate of about 39%. Red arrow-increase; blue arrow-decrease.

Roles of Signaling Pathways of Macrophages in ILD/PF in Animal Models
Regarding the relationship between macrophages and PF, several studies support the vital roles of macrophages in the pathogenesis of lung fibrosis. Macrophages in lung tissue samples from patients with fibrosis are higher compared to controls without fibrosis [33]. Macrophages play a mechanistic role in exacerbating lung fibrosis [34]. On the other hand, the ablation of macrophages was shown to significantly decrease fibroblasts and collagen deposition, ameliorating lung fibrosis [35]. Macrophages participate in both the inflammation and tissue repair phases of PF through various mechanisms, as detailed below.
(2) CCR2 axis: The CCL2/CCR2 axis is a major regulator of monocyte trafficking and plays an essential role in PF. CCR2 deficiency suppresses macrophage infiltration and reduces macrophage-derived MMP-2 and MMP-9 production, which decreases lung extracellular matrix content in the lungs (Table 1) and protects mice from PF [37].
(3) CCR4 axis: CCR4 promotes tissue injury through the induction of the M1 macrophage phenotype. In the absence of CCR4, macrophages upregulate the scavenging receptor D6, which attenuates inflammation and tissue injury (Table 1) and protects mice from lung fibrosis [38].
(4) CD204 axis: Collagen type I monomers stimulate macrophages to induce CD204 expression. In the context of elevated CD204, PF macrophages show hyperreactivity to stimulation with collagen type I monomers, resulting in exacerbated CCL18 secretion [39]. CCL18 triggers collagen production by fibroblasts. However, through β 2 -integrins and scavenger receptors, macrophages in the vicinity bind to collagen type I and increase CCL18 production. These reactions generate a feed-forward loop of augmented, ceaseless macrophage activation and unrestricted collagen production by fibroblasts (Table 1) [40].
(5) Glycolysis: Macrophages from fibrotic lungs assume the elevated expression of the glucose transporter GLUT1 [41], which augments the glycolysis required for the profibrotic profile in macrophages from fibrotic lungs (Table 1) [42]. (6) GSK pathway: TRIB3 is significantly upregulated in the macrophages of patients with PF. The TRIB3-GSK-3β interaction inhibits A20 activity and stabilizes C/EBPβ to induce macrophage activation, which triggers the transformation of lung fibroblasts into myofibroblasts, driving lung fibrosis (Table 1). Consequently, the macrophage-specific knockout of TRIB3 suppresses fibrotic changes in the lungs [43]. (7) HIF pathway: Macrophages of fibrotic lungs show increased HIF1A, which upregulates the ADORA2B receptor on macrophages. ADORA2B contributes to macrophage differentiation and the production of profibrotic mediators (Table 1), facilitating fibrosis in the lung [44]. (8) Itaconate axis: In the murine PF model, aconitate decarboxylase 1 (ACOD1) decarboxylates cis-aconitate to itaconate, and itaconate suppresses fibroblast proliferation and profibrotic activity, thereby limiting the severity of PF (Table 1). ACOD1 deficiency in macrophages induces profibrotic gene expression and worsens lung fibrosis [45]. (9) Macrophage migration: In the process of lung fibrosis, macrophages migrate into or within the lung to orchestrate and amplify fibrosis. In humans, monocyte migration is enhanced in PF. PLXNC1 is underexpressed and Syt7 is overexpressed in PF, and PLXNC1 suppresses Syt7-driven macrophage migration ( Table 1). The underexpression or absence of PLXNC1 exacerbates macrophage migration and aggravates experimentally induced lung fibrosis. Conversely, restoring PLXNC1 in macrophages is sufficient to attenuate fibrosis [46]. (10) MAPK signaling: Human fibrotic lung exhibits augmented FOXM1 expression in macrophages. FOXM1 activates DUSP1 and inhibits the p38 MAPK signaling, therefore ameliorating lung fibrosis (Table 1). In agreement with this, macrophage-specific FOXM1 knockout mice develop severe PF. On the other hand, the transfer of FOXM1-expressing monocytes protects FOXM1-deficient mice against lung fibrosis [47].
MBD2 selectively binds to the SH2-containing inositol 5 -phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].
(13) TNF pathway: STAT1 is expressed in lung macrophages [57]. STAT1 induces ICAM-1 and downstream TNF from macrophages and the subsequent infiltration of inflammatory cells and eventual fibrosis (Table 1) [58]. In agreement with this, STAT1 inhibition ameliorates collagen deposition in the lungs in an animal model [59]. In the same way, CD300c2 enhances high-mobility group box protein-1 (HMGB-1)-induced macrophage activation to produce tumor necrosis factor (TNF), which is a leukocyte chemoattractants, resulting in the accumulation of augmented immune cells, inflammation, and the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. " lated transforming growth factor-β (TGF-β) [53] (CHOP) decreases the expression of SOCS1 and SO signaling, which is essential for TGF-β product MBD2. MBD2 selectively binds to the SH2-conta moter in macrophages, by which MBD2 repr PI3K/Akt signaling to promote the macrophage M stream TGF-β [55]. In the same way, FBXW7 is a in the macrophages of pulmonary tissue fibrosis m ficiency of macrophage FBXW7 promotes the re cytes, increases the K48-linked polyubiquitination and downregulates the expression of TGF-β (T through these pathways, enhanced fibroblast diff (13) TNF pathway: STAT1 is expressed in l ICAM-1 and downstream TNF from macrophage flammatory cells and eventual fibrosis (Table 1) [5 bition ameliorates collagen deposition in the lung way, CD300c2 enhances high-mobility group bo phage activation to produce tumor necrosis facto tractants, resulting in the accumulation of augm the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF decrease, "↑"-increase. "-lead to, "↓"-decrease, "↑"-increase.

Signaling Pathways Results Reference
Caspase pathway MCU ↑ CPT1A (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production (Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].
(13) TNF pathway: STAT1 is expressed in lung macrophages [57]. STAT1 indu ICAM-1 and downstream TNF from macrophages and the subsequent infiltration o flammatory cells and eventual fibrosis ( Table 1) [58]. In agreement with this, STAT1 i bition ameliorates collagen deposition in the lungs in an animal model [59]. In the s way, CD300c2 enhances high-mobility group box protein-1 (HMGB-1)-induced ma phage activation to produce tumor necrosis factor (TNF), which is a leukocyte chem tractants, resulting in the accumulation of augmented immune cells, inflammation, the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. "→"-lead to, "↓"decrease, "↑"-increase.  (12) TGF-β signaling: There are several ways to modu ing in PF. For example, Akt-mediated reactive oxygen spe mitophagy and contributes to macrophage apoptosis resis lated transforming growth factor-β (TGF-β) [53]. Similar (CHOP) decreases the expression of SOCS1 and SOCS3, th signaling, which is essential for TGF-β production (Tab MBD2. MBD2 selectively binds to the SH2-containing ino moter in macrophages, by which MBD2 represses SH PI3K/Akt signaling to promote the macrophage M2 progra stream TGF-β [55]. In the same way, FBXW7 is an E3 ubi in the macrophages of pulmonary tissue fibrosis mice is m ficiency of macrophage FBXW7 promotes the recruitmen cytes, increases the K48-linked polyubiquitination and pr and downregulates the expression of TGF-β (Table 1) [ through these pathways, enhanced fibroblast differentiati (13) TNF pathway: STAT1 is expressed in lung mac ICAM-1 and downstream TNF from macrophages and th flammatory cells and eventual fibrosis (Table 1) [58]. In ag bition ameliorates collagen deposition in the lungs in an way, CD300c2 enhances high-mobility group box protei phage activation to produce tumor necrosis factor (TNF), tractants, resulting in the accumulation of augmented im the aggravation of lung fibrosis (Table 1) [60].  (12) TGF-β signaling: There are several ways to mod ing in PF. For example, Akt-mediated reactive oxygen s mitophagy and contributes to macrophage apoptosis res lated transforming growth factor-β (TGF-β) [53]. Simil (CHOP) decreases the expression of SOCS1 and SOCS3, signaling, which is essential for TGF-β production (T MBD2. MBD2 selectively binds to the SH2-containing i moter in macrophages, by which MBD2 represses PI3K/Akt signaling to promote the macrophage M2 prog stream TGF-β [55]. In the same way, FBXW7 is an E3 u in the macrophages of pulmonary tissue fibrosis mice is ficiency of macrophage FBXW7 promotes the recruitm cytes, increases the K48-linked polyubiquitination and p and downregulates the expression of TGF-β (Table 1) through these pathways, enhanced fibroblast differentia (13) TNF pathway: STAT1 is expressed in lung m ICAM-1 and downstream TNF from macrophages and flammatory cells and eventual fibrosis (Table 1) [58]. In bition ameliorates collagen deposition in the lungs in a way, CD300c2 enhances high-mobility group box prot phage activation to produce tumor necrosis factor (TNF tractants, resulting in the accumulation of augmented i the aggravation of lung fibrosis (Table 1) [60].  (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production ( Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].

Signaling Pathways
(13) TNF pathway: STAT1 is expressed in lung macrophages [57]. STAT1 induces ICAM-1 and downstream TNF from macrophages and the subsequent infiltration of inflammatory cells and eventual fibrosis (Table 1) [58]. In agreement with this, STAT1 inhibition ameliorates collagen deposition in the lungs in an animal model [59]. In the same way, CD300c2 enhances high-mobility group box protein-1 (HMGB-1)-induced macrophage activation to produce tumor necrosis factor (TNF), which is a leukocyte chemoattractants, resulting in the accumulation of augmented immune cells, inflammation, and the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. "→"-lead to, "↓"decrease, "↑"-increase.  (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production ( Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].

Signaling Pathways
(13) TNF pathway: STAT1 is expressed in lung macrophages [57]. STAT1 induces ICAM-1 and downstream TNF from macrophages and the subsequent infiltration of inflammatory cells and eventual fibrosis (Table 1) [58]. In agreement with this, STAT1 inhibition ameliorates collagen deposition in the lungs in an animal model [59]. In the same way, CD300c2 enhances high-mobility group box protein-1 (HMGB-1)-induced macrophage activation to produce tumor necrosis factor (TNF), which is a leukocyte chemoattractants, resulting in the accumulation of augmented immune cells, inflammation, and the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. "→"-lead to, "↓"decrease, "↑"-increase.  (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production ( Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].

Signaling Pathways
(13) TNF pathway: STAT1 is expressed in lung macrophages [57]. STAT1 induces ICAM-1 and downstream TNF from macrophages and the subsequent infiltration of inflammatory cells and eventual fibrosis (Table 1) [58]. In agreement with this, STAT1 inhibition ameliorates collagen deposition in the lungs in an animal model [59]. In the same way, CD300c2 enhances high-mobility group box protein-1 (HMGB-1)-induced macrophage activation to produce tumor necrosis factor (TNF), which is a leukocyte chemoattractants, resulting in the accumulation of augmented immune cells, inflammation, and the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. "→"-lead to, "↓"decrease, "↑"-increase.

Signaling Pathways
Results (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production ( Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].

Signaling Pathways
Results (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production ( Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].

Signaling Pathways
Results (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production ( Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].

Signaling Pathways
Results (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production ( Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].

Signaling Pathways
Results ↑ extracellular matrix deposition [37] CCR4 axis CCR4 ↑ inflammation and tissue injury ↑ fibrosis [ (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production ( Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].

Signaling Pathways
Results ↑ extracellular matrix deposition [37] CCR4 axis CCR4 ↑ inflammation and tissue injury ↑ fibrosis [ (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production ( Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].

Signaling Pathways
Results  (12) TGF-β signaling: There are several ways to modulate macropha ing in PF. For example, Akt-mediated reactive oxygen species (ROS) pro mitophagy and contributes to macrophage apoptosis resistance, which re lated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP hom (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancin signaling, which is essential for TGF-β production ( Table 1) [54]. Ano MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phospha moter in macrophages, by which MBD2 represses SHIP expression PI3K/Akt signaling to promote the macrophage M2 program and the prod stream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, w in the macrophages of pulmonary tissue fibrosis mice is markedly decrea ficiency of macrophage FBXW7 promotes the recruitment and accumu cytes, increases the K48-linked polyubiquitination and proteasome degr and downregulates the expression of TGF-β (Table 1) [56]. When TG through these pathways, enhanced fibroblast differentiation and fibrosis (13) TNF pathway: STAT1 is expressed in lung macrophages [57]. ICAM-1 and downstream TNF from macrophages and the subsequent i flammatory cells and eventual fibrosis (Table 1) [58]. In agreement with t bition ameliorates collagen deposition in the lungs in an animal model [ way, CD300c2 enhances high-mobility group box protein-1 (HMGB-1)phage activation to produce tumor necrosis factor (TNF), which is a leu tractants, resulting in the accumulation of augmented immune cells, inf the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. "→"decrease, "↑"-increase.

Signaling Pathways
Results ↑ extracellular matrix deposition CCR4 axis CCR4 ↑ inflammation and tissue injury ↑ fibrosis CD204 axis  (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production ( Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].
(13) TNF pathway: STAT1 is expressed in lung macrophages [57]. STAT1 induces ICAM-1 and downstream TNF from macrophages and the subsequent infiltration of inflammatory cells and eventual fibrosis (Table 1) [58]. In agreement with this, STAT1 inhibition ameliorates collagen deposition in the lungs in an animal model [59]. In the same way, CD300c2 enhances high-mobility group box protein-1 (HMGB-1)-induced macrophage activation to produce tumor necrosis factor (TNF), which is a leukocyte chemoattractants, resulting in the accumulation of augmented immune cells, inflammation, and the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. "→"-lead to, "↓"decrease, "↑"-increase. (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production ( Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].

Signaling Pathways
(13) TNF pathway: STAT1 is expressed in lung macrophages [57]. STAT1 induces ICAM-1 and downstream TNF from macrophages and the subsequent infiltration of inflammatory cells and eventual fibrosis (Table 1) [58]. In agreement with this, STAT1 inhibition ameliorates collagen deposition in the lungs in an animal model [59]. In the same way, CD300c2 enhances high-mobility group box protein-1 (HMGB-1)-induced macrophage activation to produce tumor necrosis factor (TNF), which is a leukocyte chemoattractants, resulting in the accumulation of augmented immune cells, inflammation, and the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. "→"-lead to, "↓"decrease, "↑"-increase. (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production ( Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].

Signaling Pathways
(13) TNF pathway: STAT1 is expressed in lung macrophages [57]. STAT1 induces ICAM-1 and downstream TNF from macrophages and the subsequent infiltration of inflammatory cells and eventual fibrosis (Table 1) [58]. In agreement with this, STAT1 inhibition ameliorates collagen deposition in the lungs in an animal model [59]. In the same way, CD300c2 enhances high-mobility group box protein-1 (HMGB-1)-induced macrophage activation to produce tumor necrosis factor (TNF), which is a leukocyte chemoattractants, resulting in the accumulation of augmented immune cells, inflammation, and the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. "→"-lead to, "↓"decrease, "↑"-increase.  (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β ing in PF. For example, Akt-mediated reactive oxygen species (ROS) production mitophagy and contributes to macrophage apoptosis resistance, which results in lated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6 signaling, which is essential for TGF-β production ( Table 1) [54]. Another exa MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SH moter in macrophages, by which MBD2 represses SHIP expression and e PI3K/Akt signaling to promote the macrophage M2 program and the production o stream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose ex in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and ficiency of macrophage FBXW7 promotes the recruitment and accumulation of cytes, increases the K48-linked polyubiquitination and proteasome degradation and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is in through these pathways, enhanced fibroblast differentiation and fibrosis ensues [ (13) TNF pathway: STAT1 is expressed in lung macrophages [57]. STAT1 ICAM-1 and downstream TNF from macrophages and the subsequent infiltratio flammatory cells and eventual fibrosis (Table 1) [58]. In agreement with this, STA bition ameliorates collagen deposition in the lungs in an animal model [59]. In t way, CD300c2 enhances high-mobility group box protein-1 (HMGB-1)-induced phage activation to produce tumor necrosis factor (TNF), which is a leukocyte c tractants, resulting in the accumulation of augmented immune cells, inflammat the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. "→"-lead to, " decrease, "↑"-increase. (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production ( Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].

Signaling Pathways
(13) TNF pathway: STAT1 is expressed in lung macrophages [57]. STAT1 induces ICAM-1 and downstream TNF from macrophages and the subsequent infiltration of inflammatory cells and eventual fibrosis (Table 1) [58]. In agreement with this, STAT1 inhibition ameliorates collagen deposition in the lungs in an animal model [59]. In the same way, CD300c2 enhances high-mobility group box protein-1 (HMGB-1)-induced macrophage activation to produce tumor necrosis factor (TNF), which is a leukocyte chemoattractants, resulting in the accumulation of augmented immune cells, inflammation, and the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. "→"-lead to, "↓"decrease, "↑"-increase.  (12) TGF-β signaling: There are several ways to modulate macrop ing in PF. For example, Akt-mediated reactive oxygen species (ROS) p mitophagy and contributes to macrophage apoptosis resistance, which lated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP h (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhan signaling, which is essential for TGF-β production ( Table 1) [54]. A MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosp moter in macrophages, by which MBD2 represses SHIP express PI3K/Akt signaling to promote the macrophage M2 program and the pr stream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase in the macrophages of pulmonary tissue fibrosis mice is markedly dec ficiency of macrophage FBXW7 promotes the recruitment and accum cytes, increases the K48-linked polyubiquitination and proteasome de and downregulates the expression of TGF-β (Table 1) [56]. When T through these pathways, enhanced fibroblast differentiation and fibro (13) TNF pathway: STAT1 is expressed in lung macrophages [5 ICAM-1 and downstream TNF from macrophages and the subsequen flammatory cells and eventual fibrosis (Table 1) [58]. In agreement wit bition ameliorates collagen deposition in the lungs in an animal mod way, CD300c2 enhances high-mobility group box protein-1 (HMGBphage activation to produce tumor necrosis factor (TNF), which is a l tractants, resulting in the accumulation of augmented immune cells, the aggravation of lung fibrosis ( (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production ( Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].

Signaling Pathways
(13) TNF pathway: STAT1 is expressed in lung macrophages [57]. STAT1 induces ICAM-1 and downstream TNF from macrophages and the subsequent infiltration of inflammatory cells and eventual fibrosis (Table 1) [58]. In agreement with this, STAT1 inhibition ameliorates collagen deposition in the lungs in an animal model [59]. In the same way, CD300c2 enhances high-mobility group box protein-1 (HMGB-1)-induced macrophage activation to produce tumor necrosis factor (TNF), which is a leukocyte chemoattractants, resulting in the accumulation of augmented immune cells, inflammation, and the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. "→"-lead to, "↓"decrease, "↑"-increase. (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production ( Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].

Signaling Pathways
(13) TNF pathway: STAT1 is expressed in lung macrophages [57]. STAT1 induces ICAM-1 and downstream TNF from macrophages and the subsequent infiltration of inflammatory cells and eventual fibrosis (Table 1) [58]. In agreement with this, STAT1 inhibition ameliorates collagen deposition in the lungs in an animal model [59]. In the same way, CD300c2 enhances high-mobility group box protein-1 (HMGB-1)-induced macrophage activation to produce tumor necrosis factor (TNF), which is a leukocyte chemoattractants, resulting in the accumulation of augmented immune cells, inflammation, and the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. "→"-lead to, "↓"decrease, "↑"-increase. (12) TGF-β signaling: There are several ways to modulate ma ing in PF. For example, Akt-mediated reactive oxygen species (R mitophagy and contributes to macrophage apoptosis resistance, w lated transforming growth factor-β (TGF-β) [53]. Similarly, C/E (CHOP) decreases the expression of SOCS1 and SOCS3, thereby en signaling, which is essential for TGF-β production ( Table 1) [5 MBD2. MBD2 selectively binds to the SH2-containing inositol 5′moter in macrophages, by which MBD2 represses SHIP exp PI3K/Akt signaling to promote the macrophage M2 program and t stream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin l in the macrophages of pulmonary tissue fibrosis mice is markedly ficiency of macrophage FBXW7 promotes the recruitment and a cytes, increases the K48-linked polyubiquitination and proteasom and downregulates the expression of TGF-β (Table 1) [56]. Wh through these pathways, enhanced fibroblast differentiation and (13) TNF pathway: STAT1 is expressed in lung macrophag ICAM-1 and downstream TNF from macrophages and the subse flammatory cells and eventual fibrosis (Table 1) [58]. In agreemen bition ameliorates collagen deposition in the lungs in an animal way, CD300c2 enhances high-mobility group box protein-1 (HM phage activation to produce tumor necrosis factor (TNF), which tractants, resulting in the accumulation of augmented immune c the aggravation of lung fibrosis (Table 1) [60]. (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β signaling in PF. For example, Akt-mediated reactive oxygen species (ROS) production induces mitophagy and contributes to macrophage apoptosis resistance, which results in upregulated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous protein (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6/PPARγ signaling, which is essential for TGF-β production ( Table 1) [54]. Another example is MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SHIP) promoter in macrophages, by which MBD2 represses SHIP expression and enhances PI3K/Akt signaling to promote the macrophage M2 program and the production of downstream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose expression in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and the deficiency of macrophage FBXW7 promotes the recruitment and accumulation of phagocytes, increases the K48-linked polyubiquitination and proteasome degradation of c-Jun, and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is increased through these pathways, enhanced fibroblast differentiation and fibrosis ensues [53].

Signaling Pathways
(13) TNF pathway: STAT1 is expressed in lung macrophages [57]. STAT1 induces ICAM-1 and downstream TNF from macrophages and the subsequent infiltration of inflammatory cells and eventual fibrosis (Table 1) [58]. In agreement with this, STAT1 inhibition ameliorates collagen deposition in the lungs in an animal model [59]. In the same way, CD300c2 enhances high-mobility group box protein-1 (HMGB-1)-induced macrophage activation to produce tumor necrosis factor (TNF), which is a leukocyte chemoattractants, resulting in the accumulation of augmented immune cells, inflammation, and the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. "→"-lead to, "↓"decrease, "↑"-increase. (12) TGF-β signaling: There are several ways to modulate macrophage TGF-β ing in PF. For example, Akt-mediated reactive oxygen species (ROS) production mitophagy and contributes to macrophage apoptosis resistance, which results in lated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP homologous (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancing STAT6 signaling, which is essential for TGF-β production ( Table 1) [54]. Another exa MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phosphatase (SH moter in macrophages, by which MBD2 represses SHIP expression and e PI3K/Akt signaling to promote the macrophage M2 program and the production o stream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, whose exp in the macrophages of pulmonary tissue fibrosis mice is markedly decreased, and ficiency of macrophage FBXW7 promotes the recruitment and accumulation of cytes, increases the K48-linked polyubiquitination and proteasome degradation o and downregulates the expression of TGF-β (Table 1) [56]. When TGF-β is in through these pathways, enhanced fibroblast differentiation and fibrosis ensues [ (13) TNF pathway: STAT1 is expressed in lung macrophages [57]. STAT1 ICAM-1 and downstream TNF from macrophages and the subsequent infiltratio flammatory cells and eventual fibrosis (Table 1) [58]. In agreement with this, STA bition ameliorates collagen deposition in the lungs in an animal model [59]. In t way, CD300c2 enhances high-mobility group box protein-1 (HMGB-1)-induced phage activation to produce tumor necrosis factor (TNF), which is a leukocyte c tractants, resulting in the accumulation of augmented immune cells, inflammati the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. "→"-lead to, " decrease, "↑"-increase.

Roles of Macrophage-Derived Secretory Proteins/microRNAs in ILD/PF in Animal Models
In addition to macrophages themselves, macrophage-derived secretory proteins and microRNAs also execute various biological functions to modulate the lung fibrotic process.
(2) AT1R: Macrophages secrete a considerable number of exosomes bearing AT1R, which are taken up by fibroblasts and result in higher levels of AT1R, the activation of the profibrotic TGF-β/Smad2/Smad3 pathway, the production of α-collagen I, and augmented Ang II secretion by fibroblasts. Interestingly, Ang II increases the number of macrophage exosomes and AT1R secretion, leading to a positive feedback between Ang II and exosome production involved in lung fibrosis (Table 2) [62].
(3) CCL6: CCL6, also called C10, is expressed in the macrophages and also attracts macrophages. Upregulated CCL6 accounts for the increased susceptibility to PF in the mice model. The neutralization of CCL6 attenuates subsequent lung fibrosis (Table 2) [63].
(4) Fibronectin: Compared to normal macrophages, PF macrophages produce more fibronectin [64]. Fibronectin transform fibroblasts to myofibroblasts, which lead to a local accumulation of extracellular matrix and hence the development of fibrosis in the lungs ( Table 2) [65].
(5) Galectin-3: Galectin-3 is produced by macrophages and the levels of galectin-3 in CTD-ILD patients are higher than in control patients. Galectin-3 induces the production of TNF-α in macrophages, and galectin-3 expression in macrophages is also induced by TNF-α, creating a self-perpetuating cycle between TNF-α and galectin-3 to support inflammation. In addition, galectin-3 stimulates fibroblasts to induce proliferation ( Table 2). All these changes promote lung fibrosis [66].
(12) S100A4: M2-polarized macrophages secrete S100A4, which stimulates the proliferation and activation of fibroblasts and is increased in PF ( Table 2). The inhibition of S100A4 reduces histological evidence of lung fibrosis [75].

Molecules Characteristics Signaling Pathway Reference
Macrophage-derived secretory proteins/microRNAs that aggravate ILD/PF ADAM17 Protein ↑ shedding of mIL-6Rα stream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin in the macrophages of pulmonary tissue fibrosis mice is marke ficiency of macrophage FBXW7 promotes the recruitment an cytes, increases the K48-linked polyubiquitination and proteas and downregulates the expression of TGF-β (Table 1) [56]. through these pathways, enhanced fibroblast differentiation an (13) TNF pathway: STAT1 is expressed in lung macroph ICAM-1 and downstream TNF from macrophages and the su flammatory cells and eventual fibrosis (Table 1) [58]. In agreem bition ameliorates collagen deposition in the lungs in an anim way, CD300c2 enhances high-mobility group box protein-1 ( phage activation to produce tumor necrosis factor (TNF), whi tractants, resulting in the accumulation of augmented immun the aggravation of lung fibrosis (Table 1) [60]. stream TGF-β [55]. In the same way, FBX in the macrophages of pulmonary tissue ficiency of macrophage FBXW7 promote cytes, increases the K48-linked polyubiqu and downregulates the expression of T through these pathways, enhanced fibrob (13) TNF pathway: STAT1 is expres ICAM-1 and downstream TNF from mac flammatory cells and eventual fibrosis (T bition ameliorates collagen deposition in way, CD300c2 enhances high-mobility g phage activation to produce tumor necro tractants, resulting in the accumulation o the aggravation of lung fibrosis (Table 1)  lated transforming growth factor-β (TGF-β) [53]. Similarly, C/E (CHOP) decreases the expression of SOCS1 and SOCS3, thereby signaling, which is essential for TGF-β production (  [64,65] Galectin-3 Protein ↑ TNF-α mitophagy and contributes to macrophage apoptosis resistance, which r lated transforming growth factor-β (TGF-β) [53]. Similarly, C/EBP hom (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhancin signaling, which is essential for TGF-β production ( Table 1) [54]. Ano MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-phospha moter in macrophages, by which MBD2 represses SHIP expression PI3K/Akt signaling to promote the macrophage M2 program and the prod stream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin ligase, w in the macrophages of pulmonary tissue fibrosis mice is markedly decrea ficiency of macrophage FBXW7 promotes the recruitment and accumu cytes, increases the K48-linked polyubiquitination and proteasome degr and downregulates the expression of TGF-β (Table 1) [56]. When TG through these pathways, enhanced fibroblast differentiation and fibrosis (13) TNF pathway: STAT1 is expressed in lung macrophages [57] ICAM-1 and downstream TNF from macrophages and the subsequent flammatory cells and eventual fibrosis (Table 1) [58]. In agreement with bition ameliorates collagen deposition in the lungs in an animal model way, CD300c2 enhances high-mobility group box protein-1 (HMGB-1) phage activation to produce tumor necrosis factor (TNF), which is a leu tractants, resulting in the accumulation of augmented immune cells, in the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. "→"-decrease, "↑"-increase.

Signaling Pathways Results
Caspase pathway mitophagy and contributes to macrophage apoptosis resista lated transforming growth factor-β (TGF-β) [53]. Similarly (CHOP) decreases the expression of SOCS1 and SOCS3, ther signaling, which is essential for TGF-β production (Table  MBD2. MBD2 selectively binds to the SH2-containing inosi moter in macrophages, by which MBD2 represses SHI PI3K/Akt signaling to promote the macrophage M2 program stream TGF-β [55]. In the same way, FBXW7 is an E3 ubiqu in the macrophages of pulmonary tissue fibrosis mice is ma ficiency of macrophage FBXW7 promotes the recruitment cytes, increases the K48-linked polyubiquitination and prot and downregulates the expression of TGF-β (  [53]. Similarly, C/EBP (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enh signaling, which is essential for TGF-β production ( Table 1) [54] MBD2. MBD2 selectively binds to the SH2-containing inositol 5′-ph moter in macrophages, by which MBD2 represses SHIP expre PI3K/Akt signaling to promote the macrophage M2 program and the stream TGF-β [55]. In the same way, FBXW7 is an E3 ubiquitin liga in the macrophages of pulmonary tissue fibrosis mice is markedly d ficiency of macrophage FBXW7 promotes the recruitment and acc cytes, increases the K48-linked polyubiquitination and proteasome and downregulates the expression of TGF-β (Table 1) [56]. When through these pathways, enhanced fibroblast differentiation and fib (13) TNF pathway: STAT1 is expressed in lung macrophages ICAM-1 and downstream TNF from macrophages and the subsequ flammatory cells and eventual fibrosis (Table 1) [58]. In agreement w bition ameliorates collagen deposition in the lungs in an animal m way, CD300c2 enhances high-mobility group box protein-1 (HMG phage activation to produce tumor necrosis factor (TNF), which is tractants, resulting in the accumulation of augmented immune cel the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. " decrease, "↑"-increase.

Signaling Pathways Results
Caspase pathway  [68,69] MIP-1α Protein ↑ leukocyte accumulation (12) TGF-β signaling: There are several ways to mo ing in PF. For example, Akt-mediated reactive oxygen mitophagy and contributes to macrophage apoptosis re lated transforming growth factor-β (TGF-β) [53]. Simi (CHOP) decreases the expression of SOCS1 and SOCS3, signaling, which is essential for TGF-β production (T MBD2. MBD2 selectively binds to the SH2-containing moter in macrophages, by which MBD2 represses PI3K/Akt signaling to promote the macrophage M2 pro stream TGF-β [55]. In the same way, FBXW7 is an E3 u in the macrophages of pulmonary tissue fibrosis mice i ficiency of macrophage FBXW7 promotes the recruitm cytes, increases the K48-linked polyubiquitination and and downregulates the expression of TGF-β (Table 1 through these pathways, enhanced fibroblast differenti (13) TNF pathway: STAT1 is expressed in lung m ICAM-1 and downstream TNF from macrophages and flammatory cells and eventual fibrosis (Table 1) [58]. In bition ameliorates collagen deposition in the lungs in a way, CD300c2 enhances high-mobility group box pro phage activation to produce tumor necrosis factor (TN tractants, resulting in the accumulation of augmented the aggravation of lung fibrosis (Table 1) [60].  [53]. Similarly, C/EBP ho (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enhanc signaling, which is essential for TGF-β production (  [58]. In agreement wit bition ameliorates collagen deposition in the lungs in an animal mode way, CD300c2 enhances high-mobility group box protein-1 (HMGB-phage activation to produce tumor necrosis factor (TNF), which is a le tractants, resulting in the accumulation of augmented immune cells, the aggravation of lung fibrosis (Table 1) [60]. Table 1. Signaling pathways of macrophages in ILD/PF in animal models. "→" decrease, "↑"-increase.

Signaling Pathways Results
Caspase pathway  [53]. Similarly, C/E (CHOP) decreases the expression of SOCS1 and SOCS3, thereby e signaling, which is essential for TGF-β production (  (12) TGF-β signaling: There are several ways to modulat ing in PF. For example, Akt-mediated reactive oxygen specie mitophagy and contributes to macrophage apoptosis resistan lated transforming growth factor-β (TGF-β) [53]. Similarly, (CHOP) decreases the expression of SOCS1 and SOCS3, there signaling, which is essential for TGF-β production ( Table 1 MBD2. MBD2 selectively binds to the SH2-containing inosito moter in macrophages, by which MBD2 represses SHIP PI3K/Akt signaling to promote the macrophage M2 program a stream TGF-β [55]. In the same way, FBXW7 is an E3 ubiqui in the macrophages of pulmonary tissue fibrosis mice is mark ficiency of macrophage FBXW7 promotes the recruitment a cytes, increases the K48-linked polyubiquitination and prote and downregulates the expression of TGF-β (Table 1) [56] through these pathways, enhanced fibroblast differentiation a (13) TNF pathway: STAT1 is expressed in lung macrop ICAM-1 and downstream TNF from macrophages and the s flammatory cells and eventual fibrosis (Table 1) [58]. In agree bition ameliorates collagen deposition in the lungs in an ani way, CD300c2 enhances high-mobility group box protein-1 phage activation to produce tumor necrosis factor (TNF), wh tractants, resulting in the accumulation of augmented immu the aggravation of lung fibrosis (Table 1) [60].  [53]. Similarly, C/EBP (CHOP) decreases the expression of SOCS1 and SOCS3, thereby enha signaling, which is essential for TGF-β production (  [53]. Similarly, C/EB (CHOP) decreases the expression of SOCS1 and SOCS3, thereby en signaling, which is essential for TGF-β production (

Roles of Macrophages in CTD-ILD
The evidence mentioned above suggests that macrophages actively participate in the pathogenesis of ILD/PF. In theory, macrophages could also analogously take part in the course of CTD-ILD. This is supported by several observations.

Macrophages in Dermatomyositis (DM)-Associated ILD (DM-ILD)
Although there are no animal models that directly address the molecular mechanisms through which macrophages contribute to DM-ILD, several studies provide indirect evidence implicating macrophages as the main player in DM-ILD. Pathological analyses show that the infiltration of CD163-positive macrophages into the alveolar spaces is more severe in fatal DM-ILD than in DM-ILD survivors [83], and increased serum CD163 levels are associated with a higher mortality rate in DM-ILD [84]. Similarly, CD206-positive macrophages accumulate more densely in fatal cases of DM-ILD than in DM-ILD survivors, and elevated serum CD206 levels are associated with a higher mortality rate in DM-ILD [84]. Additionally, macrophages express resistin, which is significantly higher in DM-ILD than in DM patients without ILD. Compared with chronic ILD, resistin levels are significantly elevated in rapidly progressive ILD. Acting via nuclear factor kappa B (NFκB) signaling, resistin upregulates IL-1, IL-6, and TNF-α in human monocytes. These proinflammatory cytokines induce resistin expression in macrophages (Figure 2), triggering a self-sustained loop for lung injury [85]. Together, these studies highlight the contribution of macrophages to DM-ILD. Resistin activates the NFκB signaling pathway, increasing the secretion of IL-1, IL-6, and TNF-α. This triggers the expression of resistin in macrophages, creating a self-perpetuating reaction to mediate the inflammatory pathogenesis of DM-ILD. In MPA-ILD, macrophages secrete CCL2, which attracts more macrophages to infiltrate. The recruited macrophages produce CCL2, initiating a self-propagating response. Meanwhile, CCL2 stimulates fibroblast differentiation into myofibroblasts and generates ECM, leading to exaggerated lung fibrosis. In RA-ILD, macrophages are implicated in three ways: (1) Exaggerated IL-6 secretion by macrophages triggers the proliferation of GM-CSF-producing T cells, and GM-CSF recruits neutrophil infiltration into the lung, leading to RA-ILD progression.
(2) Macrophage-derived SDC2 interferes with PI3K/Akt signaling, decreases PAD2 in fibroblasts, and reduces collagen deposition in the lungs. (3) Macrophages produce high levels of TNF, which leads to an inflammatory phase predominated by cellular infiltration into the lungs and a subsequent shift to a fibrotic phase with irreversible collagen deposition. In SSc-ILD, six pathways are activated by macrophages to drive SSc-ILD: (1) Macrophages produce increased CCL18, which facilitates collagen production. (2) Macrophages release increased fibronectin, which induces fibroblast proliferation and collagen deposition. (3) Immune complexes stimulate the production of M-CSF and IL-6, which further induce OPN from monocytes. In turn, OPN triggers fibroblast migration, driving fibrosis progression. (4) SSc-ILD shows decreased PLXNC1 expression in macrophages, which boosts macrophage migration. (5) RGC32 promotes iNOS/IL-1β-directed inflammation through NFκB signaling and subsequently enhances the fibrotic response. (6) Macrophage-derived YKL-40, which is increased in SSc-ILD, promotes fibroblast proliferation. Red arrow-increase; Blue arrow-decrease; Black arrow-lead to.

Macrophages in Microscopic Polyangiitis (MPA)-Associated ILD (MPA-ILD)
In MPA-ILD, macrophage polarization is skewed toward M2, which recruits fibroblasts and transforms them into myofibroblasts, culminating in the formation of lung fibrosis [86]. In the process of M2 polarization, the infiltrated macrophages produce CCL2, which recruits more macrophages to infiltrate the alveolar spaces. The recruited macrophages secrete CCL2, promoting a vicious cycle (Figure 2). In addition, in concert with PDGF secreted by vascular endothelial cells, CCL2 promotes myofibroblast differentiation and ECM production ( Figure 2), leading to lung fibrosis [87]. Collectively, these findings implicate macrophages in the pathogenesis of MPA-ILD.

Macrophages in Rheumatoid Arthritis (RA)-Associated ILD (RA-ILD)
In RA-ILD, autoimmune/complement/interferon cascade genes are altered in macrophages, which might contribute to profibrotic inflammatory lung responses [88]. Several molecules produced by macrophages have been highlighted in the literature (Figure 2).
In RA-ILD, macrophages produce higher IL-6, which promotes the expansion of GM-CSF-producing T cells. GM-CSF is a strong inducer of neutrophil infiltration into the lung and contributes to the progression of RA-ILD in an animal model ( Figure 2) [89]. SDC2 in macrophages activates CD148 in fibroblasts, inhibits PI3K/Akt signaling, downregulates PAD2 in fibroblasts, and attenuates collagen production by fibroblasts ( Figure 2). The overexpression of SDC2 in alveolar macrophages decreases collagen deposition in the lungs and protects mice from RA-ILD [90]. The augmented secretion of TNF by alveolar macrophages from RA-ILD has been noted [91]. TNF induces an inflammatory phase that is predominated by cellular infiltration to the pulmonary tissue, which subsequently transitions to a fibrotic phase that constitutes the "irreversible" process of collagen deposition in the pulmonary parenchyma, resulting in RA-ILD in a murine model ( Figure 2) [92].

Macrophages in Systemic Sclerosis (SSc)-Associated ILD (SSc-ILD)
In SSc-ILD, macrophages express profibrotic factors that promote the differentiation, migration, and activation of fibroblasts, suggesting the involvement of macrophages in SSc-ILD [25]. Currently, there are several known mechanisms that macrophages utilize to modulate SSc-ILD ( Figure 2). (1) Monocytes from SSc-ILD patients reveal a profibrotic phenotype characterized by the expression of CD163 and the enhanced secretion of CCL18 [93], which promotes collagen production ( Figure 2) [40]. (2) At the same time, SSc-ILD macrophages release significantly more fibronectin, which leads to fibroblast proliferation and subsequent collagen deposition ( Figure 2) [64,93]. (3) Immunologically, immune complexes (ICs) activate human monocytes to secrete M-CSF and IL-6, which in turn induce osteopontin (OPN) from monocytes. Next, OPN facilitates fibroblast migration to areas adjacent to the fibrotic niche, thereby aiding lung fibrosis progression (Figure 2) [94]. (4) Meanwhile, PLXNC1 expression is reduced in SSc-ILD macrophages, which could lead to the excess migration of macrophages (Figure 2), amplifying fibrosis [46]. (5) Moreover, the response gene to complement 32 (RGC32) is abundantly expressed in macrophages, activates NFκB signaling, and promotes inflammatory gene expression by binding to their promoters. RGC32 deficiency in mice impairs the polarization of classically activated macrophages, attenuates the expression of inflammatory mediators in macrophages, including the fibrosis inducers iNOS and IL-1β, which are regulated by NFκB, and significantly ameliorates lung fibrosis (Figure 2) [95]. (6) YKL-40 is elevated in SSc-ILD. Macrophages produce YKL-40, which exerts promitogenic effects on lung fibroblasts (Figure 2) [96]. These findings all support the central roles of macrophages in SSc-ILD.

Targeting Macrophages in CTD-ILD
It is hoped that, apart from detailing our current understanding of CTD-ILD pathogenesis, this knowledge could be leveraged to create therapeutic strategies to combat CTD-ILD. However, similar to the understanding of disease pathogenesis, most therapeutic strategies that target macrophages in CTD-ILD originated from studies targeting macrophages in PF. Therefore, in the following section, we review therapeutic strategies to target macrophages in preclinical or clinical models of PF or CTD-ILD ( Figure 3): As a result, ABT-199 augments caspase-3 activity and enhances macrophage apoptosis, counteracting lung fibrosis. (2) Anti-IL-33 blocks IL-33 action on ST2 and thereby downregulates IL-13 and TGF-β1 production, which decreases collagen synthesis by fibroblasts. (3) Clevudine, as an inhibitor of the PI3K/Akt signaling pathway, prevents M2 polarization and the subsequent fibrotic response of the lungs. (4) By inhibiting Cu,Zn-SOD-mediated H 2 O 2 generation, leflunomide downregulates Jmjd3 expression, lowers M2 polarization, and diminishes lung fibrosis. (5) GW4869, which eliminates the secretion of AT1R-carrying exosomes from macrophages, decreases collagen synthesis in fibroblasts and ameliorates lung fibrosis. (6) IL-10 curbs TGF-β production in macrophages and prevents collagen deposition by fibroblasts. (7) Methyl palmitate blocks IκBα phosphorylation, reducing TNF-α and boosting IL-10 expression in macrophages, which inhibit lung inflammation and fibrosis. (8) After binding to GRP78, microcystin-LR interferes with UPR signaling, subsequently preventing M2 macrophage polarization and leading to attenuated lung fibrosis. (9) Niclosamide interferes with S100A4 production by macrophages, which ameliorates collagen production by fibroblasts. These changes culminate in reducing the fibrosis of the lungs. (10) Nintedanib limits M2 differentiation by blocking CSF1R and consequently improves fibrosis in a CTD-ILD model. (11) Pirfenidone acts on macrophages to block M2 polarization and, as a result, suppresses fibroblast proliferation and restricts lung fibrosis. (12) The β-catenin pathway inhibitor PRI-724, which blocks β-catenin signaling, lowers TGF-β production in macrophages and contributes to mitigated collagen production by fibroblasts. (13) rhPTX-2 prevents M2 differentiation and avoids PF deterioration. (14) Schisandra reduces TGF-β and downstream Smad3/Smad4 while stimulating Smad7 production. These signaling events disrupt M2 polarization and thereby improving lung fibrosis. (15) Ruxolitinib and (16) Tacrolimus, by inhibiting JAK/STAT signaling, suppress M2 polarizations and hence improve lung fibrosis in an animal model. Red arrowincrease; blue arrow-decrease; cross symbol-block; dashed line-act on.

Investigational Agents in Preclinical and Clinical Trials of CTD-ILD
In practice, there is no standard treatment protocol for CTD-ILD. However, considering the autoimmune nature of CTDs, immunomodulatory drugs are the cornerstones in the pharmacologic treatment of CTD-ILD [109]. Considering these uncertainties, therapies that address the ILD component of CTD are currently a field of active research [110]. According to clinicaltrials.gov (accessed on 25 March 2023), 39 clinical trials exploring the therapeutic effects of various agents for CTD-ILD have been planned or are already underway or completed (Table 3). Of the 16 therapeutic agents that act on non-macrophage cells, three (Cyclophosphamide, Mycophenolate Mofetil, and Tadalafil) exhibit therapeutic effects. Of the four therapeutic agents which act on macrophages, three (Nintedanib, Pirfenidone, and Tacrolimus) exhibit therapeutic effects, which is borderline higher than the percentage of agents which act on non-macrophage cells (p = 0.06 by Fisher's Exact Test). However, most available clinical trials examined agents which act on non-macrophage cells (25 clinical trials) rather than agents that act on macrophage cells (14 clinical trials). Therefore, it is hoped that future clinical trials will focus more on macrophage-directed agents.

Concluding Remarks and Future Directions
Despite the significant morbidities and mortalities caused by CTD-ILD, publications detailing how macrophages contribute to ILD in the context of CTD are scarce. More research is necessary to elucidate the distinct roles of specific lung macrophage populations in the CTD-ILD, with the aim of providing new insights into the development of macrophage-directed therapeutic targets and diagnostic tools [31]. Current knowledge is mostly extrapolated from findings on animal models of PF. However, well-established mouse macrophage counterparts might not always be available in humans. A humanized mouse model in which mice are transplanted with alveolar organoids and hematopoietic stem and progenitor cells could be exploited to overcome these issues [69]. Blocking macrophage molecular mechanisms, boosting macrophage signaling pathways, or combinations of these may prove fruitful and provide opportunities to relieve the paucity of proven effective treatments [137] and meet the clinical needs of CTD-ILD. The literature shows that aiming at specific cell types is a viable choice for several disease entities [138][139][140], especially CTDs [141,142]. Several systemic reviews also suggest the therapeutic potential of targeting specific cells in CTD-ILD [143,144]. Moreover, the pathogenesis of CTD-ILD involves other cell types (such as lymphocytes and fibroblasts) whose crosstalk with macrophages requires further characterization [74]. Deciphering these interactions could be another direction of research. We hope that our efforts to elucidate the pathophysiology of ILD macrophages in the context of CTD will offer new insights into the development of macrophage-directed therapeutic approaches for this group of debilitating diseases.